| Autor: |
Zaher ElBeck, Mohammad Bakhtiar Hossain, Humam Siga, Nikolay Oskolkov, Fredrik Karlsson, Julia Lindgren, Anna Walentinsson, Dominique Koppenhöfer, Rebecca Jarvis, Roland Bürli, Tanguy Jamier, Elske Franssen, Mike Firth, Andrea Degasperi, Claus Bendtsen, Robert I. Menzies, Katrin Streckfuss-Bömeke, Michael Kohlhaas, Alexander G. Nickel, Lars H. Lund, Christoph Maack, Ákos Végvári, Christer Betsholtz |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
|
| Zdroj: |
Nature Communications, Vol 15, Iss 1, Pp 1-23 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2041-1723 |
| DOI: |
10.1038/s41467-024-46384-8 |
| Popis: |
Abstract While excessive production of reactive oxygen species (ROS) is a characteristic hallmark of numerous diseases, clinical approaches that ameliorate oxidative stress have been unsuccessful. Here, utilizing multi-omics, we demonstrate that in cardiomyocytes, mitochondrial isocitrate dehydrogenase (IDH2) constitutes a major antioxidative defense mechanism. Paradoxically reduced expression of IDH2 associated with ventricular eccentric hypertrophy is counterbalanced by an increase in the enzyme activity. We unveil redox-dependent sex dimorphism, and extensive mutual regulation of the antioxidative activities of IDH2 and NRF2 by a feedforward network that involves 2-oxoglutarate and L-2-hydroxyglutarate and mediated in part through unconventional hydroxy-methylation of cytosine residues present in introns. Consequently, conditional targeting of ROS in a murine model of heart failure improves cardiac function in sex- and phenotype-dependent manners. Together, these insights may explain why previous attempts to treat heart failure with antioxidants have been unsuccessful and open new approaches to personalizing and, thereby, improving such treatment. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
|
Full text from SpringerLink